Stabilization of Vitamin B12

ABSTRACT

The invention relates to preparations comprising vitamin B 12  and a butanol, and to the use of butanol for stabilizing vitamins.

REFERENCE TO RELATED APPLICATIONS

This application is a division of U.S. patent application Ser. No.12/951,581, filed Nov. 22, 2010, which is a division of U.S. patentapplication Ser. No. 12/045,831, filed Mar. 11, 2008, now abandoned, andclaims priority to German Application No. DE 102007012644.3, filed Mar.16, 2007, the entire disclosures of which are incorporated herein byreference.

FIELD OF THE INVENTION

The invention relates to preparations comprising vitamin B₁₂ and abutanol, and to the use of butanol for stabilizing vitamins.

BACKGROUND OF THE INVENTION

It is generally known that vitamins are not very stable and degradationis to be observed for example on storage. This also applies to theso-called B vitamins, explicitly vitamin B₁₂. For this reason, therehave been very many studies on the topic of the stabilization ofvitamins and of vitamin B₁₂. A simple solution to this problem is forexample separating the vitamin B₁₂ from substances which promote itsdegradation. Thus, for example, JP200612486 describes 3 partialsolutions in which individual partial formulations are present. VitaminB₁₂ is stabilized not only in liquid formulations, but also in tabletsor granules, as described for example in EP416773. Most of the studieson the stabilization of vitamin B₁₂ relate however to liquidformulations. Such solutions can also be used to fill capsules(FR1472901), or the solutions are freeze dried for further stabilization(JP63313736). Among the vitamin B₁₂ solutions ready for use there aresome stabilized by the addition of iron salts (FR1285213, GB902377). Thesolutions may likewise comprise EDTA (ethylenediaminetetraacetic acid,U.S. Pat. No. 2,939,821 or GB822127). Alkali metal salts or alkalineearth metal salts are also said to have a stabilizing effect on vitaminB₁₂ (U.S. Pat. No. 2,566,123). Vitamins can also take place by use ofamino acids (U.S. Pat. No. 2,748,054) or by cyclodextrins (JP4049239),as well as by ammonium sulphate (U.S. Pat. No. 2,778,771), by sodiumiodide (JP41007474), potassium cyanide (GB692968), maleic acid(JP64011864), thiopropionic acid (U.S. Pat. No. 2,579,679),gluconolactone (ES247522), lecithins (JP55049313), urea (JP43010862) orelse by fatty acid esters with cysteine (U.S. Pat. No. 2,662,048) or byantioxidants (DE25222187) and so-called chelating agents (WO97/31620).Even solutions in N-methylpyrrolidone DE3337304 are described, in whichvitamin B₁₂ is said to be stable. In some studies, vitamin B₁₂ isstabilized through the use of polyvalent alcohols (JP2311417,JP63313736, JP05124967, FR1263794, JP04-235925, JP2000-319186 orHU150885). The use of alcohols for stabilizing vitamin B₁₂ is proposedgenerally in JP2005247800, WO2005/094842, WO02/02145, BE576619 orJP02145521. US2005074443 describes long-chain alcohols for stabilizingvitamin B₁₂. However, vitamin B₁₂ itself is also used in turn tostabilize other substances (JP2001-048780, JP2005-015368).

Thus, in JP46-15320 propylene glycol is employed for isotonicity andbenzyl alcohol as analgesic. The actual stabilization is achieved bydextran and gelatin (hydrophilic macromolecules). In JP45-011919, thealcohols propylene glycol, benzyl alcohol, mannitol or glycerol aredescribed for stabilizing 5,6-dimethylbenzimidazolyl cobamide coenzyme.

A possible way of stabilizing vitamin B₁₂ through the use of butanol hasbeen found. Although JP2005247800 mentions alcohols for stabilizingvitamin B₁₂, for example the chlorobutanol contained therein isunsuitable specifically for the solution used in this case and is, onthe contrary, harmful. Likewise, the benzyl alcohol contained inJP46-15320 or JP45-011919 is distinctly disadvantageous for theformulation described herein, because benzyl alcohol cannot bemetabolized by all animals (EMEA, Committee for veterinary medicinalproducts, summary report, benzyl alcohol, 1997) and formulations withbenzyl alcohol therefore cannot be employed as widely as formulationswith butanol.

SUMMARY OF THE INVENTION

The invention relates to:

-   -   A preparation comprising vitamin B₁₂ and butanol.    -   The use of such a preparation for the manufacture of a        medicament.    -   The use of butanol for stabilizing vitamin B₁₂.    -   The use of butanol for producing preparations of vitamin B₁₂        with improved vitamin B₁₂ stability.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a comparison of the photostabilities of a formulation withoutn-butanol (A) with a formulation with n-butanol (B), according toExample 1.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

Vitamin B₁₂ in the narrower sense frequently means cyanocobalamin, butthere are also other compounds which are likewise covered by the genericterm vitamin B₁₂; these are also referred to as cobalamins. It isintended herein that the term vitamin B₁₂ generally means all compoundswhich act as coenzyme in the human and/or animal body or can beconverted into the corresponding coenzyme forms. These vitamin B₁₂compounds have in common the Corrin structure with a trivalent cobalt ascentral atom and with a 5,5-dimethylbenzimidazole residue which isalpha-glycosidically linked via D-ribofuranose 3-phosphate. Mostcobalamins differ from one another merely in one axial substituent.Examples of compounds which can be employed as vitamin B₁₂ are:cyanocobalamin (axial substituent=CN), aquocobalamin (B_(12a), axialsubstituent=—O⁺H₂), hydroxocobalamin (B_(12b), axial substituent=—OH),nitritocobalamin (B_(12c); axial substituent=—NO₂);5‘-deoxyadenosylcobalamin (coenzyme B₁₂, axialsubstituent=5’-deoxyadenosyl) and methylcobalamin (methyl B₁₂, axialsubstituent=—CH₃). Adenosylcobalamin and methylcobalamin are the realactive forms (coenzyme forms), and aquocobalamin and hydroxocobalaminare storage forms which likewise occur in the body.

According to a preferred embodiment, the preparations according to theinvention additionally comprise a pharmacologically acceptablephosphonic acid derivative. Pharmacologically acceptable phosphonic acidderivatives which can be employed according to the invention arenormally organic compounds which are suitable as metabolic stimulantsand tonics in particular for productive and domestic animals. Preferredexamples which may be mentioned are the compounds butaphosphan andtoldimfos which have been known for a long time and are used inter aliafor mineral supplementation (phosphorus).

Butaphosphan has the chemical name(1-butylamino-1-methyl)ethylphosphonic acid and has the structuralformula

Butaphosphan is normally employed as free acid.

Toldimfos has the chemical name (4-dimethylamino-o-tolyl)phosphonic acidand has the following structural formula

Toldimfos is normally employed as sodium salt.

The present invention encompasses both the use of the free activeingredients and of their pharmaceutically acceptable salts, and the useof the corresponding hydrates and solvates of the compounds or theirsalts.

Vitamin B₁₂ is typically employed in the medicaments according to theinvention in a proportion of from 0.00001 to 0.1%, preferably 0.0001 to0.05% and particularly preferably from 0.001 to 0.01%. Here andhereinafter—unless indicated otherwise—the percentage data mean percent(M/V). This means: mass of the relevant substance in grams per 100 ml offinished solution.

Butanol refers to isomeric aliphatic alcohols which have an alkyl chainwith four carbon atoms; they may be linear or branched, specifically asn-butanol, sec-butanol, tert-butanol and isobutanol. Isobutanol andn-butanol are preferred, and especially n-butanol.

Butanol is normally employed in concentrations of from 0.1 to 10%,preferably from 0.5 to 7% and particularly preferably from 1 to 5%. Thepercentage data mean % (M/V).

The pharmacologically active phosphonic acids, such as, for example,toldimfos or, in particular, butaphosphan, are employed in themedicaments according to the invention in a proportion of from 0.1 to40%, preferably 1 to 30% and particularly preferably 5 to 20%.

The preparations according to the invention are preferably liquid andnormally comprise water or a water-miscible substance as solvent.Examples which may be mentioned are glycerol, propylene glycol,polyethylene glycols, tolerated alcohols such as ethanol or benzylalcohol, N-methylpyrrolidone, propylene carbonate, glycofurol,dimethylacetamide, 2-pyrrolidone, isopropylideneglycerol, orglycerolformal. The solvents can also be employed in mixtures orcombinations. Water-based formulations are preferred and may, of course,comprise further solvents and cosolvents.

The liquid formulation may comprise as solvent apart from water orwater-miscible substances also oils in the form of an emulsion. Mentionmay be made in this connection of vegetable, animal and synthetic oilssuch as cottonseed oil, sesame oil, soya oil, medium chain triglyceridesof a chain length of C₁₂-C₁₈, propylene glycol octanoate decanoate orelse paraffin.

The solvent (or solvent mixture) is normally present in concentrationsof up to 98%, preferably up to 90%, particularly preferably up to 87%.The concentrations of the solvent are ordinarily over 65%, preferablyover 75%, particularly preferably over 85%. The percentage data mean %(M/V).

The formulations according to the invention may also comprisecosolvents, specifically and preferably when the formulations comprisewater; the cosolvents may improve the solubility of certain ingredientsof the formulation. The cosolvents are normally employed in proportionsof from 0.1 to 30%, preferably from 1 to 10% (percentage data in eachcase M/V). Examples of cosolvents which may be mentioned are:pharmaceutically acceptable alcohols, dimethyl sulphoxide, ethyllactate, ethyl acetate, triacetin. Mixtures of the aforementionedsolvents can also be employed as cosolvent. In some circumstances,individual cosolvents can also be employed as solvents. Normally, thecosolvents employed in the preparations according to the invention areonly those which have not been already used as solvent or in the solventmixture.

Preservatives may be present in the liquid formulation. Examples whichmay be mentioned of preservatives which can be used are: aliphaticalcohols such as benzyl alcohol, ethanol, n-butanol, phenol, cresols,chlorobutanol, para-hydroxybenzoic esters (especially the methyl andpropyl esters), salts or the free acids of carboxylic acids such assorbic acid, benzoic acid, lactic acid or propionic acid. Likewise thequaternary ammonium compounds such as, for example, benzalkoniumchloride, benzethonium chloride or cetylpyridinium chloride.Preservatives are normally employed in proportions of from 0.001 to 5%,preferably from 0.01 to 4%. Where the preparations according to theinvention already comprise in sufficient quantity a component which mayserve as preservative (e.g. n-butanol), normally no additionalproportion is added for preservation purposes. It is, however, whereappropriate possible to add other preservatives also.

Depending on the nature of the formulation and administration form, themedicaments according to the invention may comprise further customary,pharmaceutically acceptable additives and excipients. Examples which maybe mentioned are

Antioxidants such as, for example, sulphites (Na sulphite, Nametabisulphite), organic sulphides (cystine, cysteine, cysteamine,methionine, thioglycerol, thioglycolic acid, thiolactic acid), phenols(tocopherols, as well as vitamin E and derivatives thereof, e.g. vitaminE TPGS (d-alpha-tocopheryl polyethylene glycol 1000 succinate)),butylhydroxyanisole, butylhydroxytoluene, octyl and dodecyl gallate),organic acids (ascorbic acid, citric acid, tartaric acid, lactic acid)and their salts and esters. Normally, 0.01-5, preferably 0.05-1, % areemployed.

Wetting agents such as, for example, fatty acid salts, fatty alkylsulphates, fatty alkylsulphonates, linear alkylbenzenesulphonates, fattyalkyl polyethylene glycol ether sulphates, fatty alkyl polyethyleneglycol ethers, alkylphenol polyethylene glycol ethers, alkylpolyglycosides, fatty acid N-methylglucamides, polysorbates, sorbitanfatty acid esters and poloxamers. Normally 0.01-10%, preferably 0.1-5%,are employed.

Substances for isotonicity such as, for example, sodium chloride,glucose or glycerol. Normally 0.01-5%, preferably 0.1-1%, are employed.

Substances able to prevent particle formation; e.g. poloxamers,lecithins, polyvinylpyrrolidones, cosolvents, antioxidants such as, forexample, sodium disulphite or complexing agents such as, for example,the sodium salt of editic acid. Normally 0.01-5%, preferably 0.05-1%,are employed.

The liquid formulations may comprise substances which improve localtolerability on administration. Examples which may be mentioned are:radical scavengers or antioxidants such as, for example, vitamin E, orvitamin C, butylhydroxyanisole, butylhydroxytoluene, cysteamine,cysteine, glutathione, thioglycol, thiolactic acid, sodium disulphide orelse acetylcysteine. Complexing agents such as, for example,cyclodextrins (e.g. hydroxypropylcyclodextrin), sodium EDTA(ethylenediaminetetraacetic acid), polyvinylpyrrolidone, dexpanthenol,salts of fatty acids such as, for example, sodium caprylate, salts ofmultiply charged metal cations (e.g. Me²⁺ or Me³⁺), especially of thealkaline earth metals, amino acids and, of these, in particular arginineor lysine, poloxamers, poloxamines, solvents or cosolvents such as, forexample, glycerol, polyethylene glycol, propylene glycol ordimethylacetamide, dextrans, creatine, creatinine, acids such as, forexample, gluconolactonic acid, lactic acid, embonic acid, citric acid,tartaric acid, mucic acid or hyaluronic acid, lecithins with aphosphatidylcholine content of 70-100% from soya or egg white. Normally,0.01-20%, preferably 0.1-10%, are employed.

Pharmaceutically acceptable colorants such as, for example, iron oxides,carotenoids, etc. Normally, 0.01-10%, preferably 0.1-5% are employed.

The pH of the liquid preparations is 2-11, preferably 3-8 andparticularly preferably 4-7. The pH is adjusted where appropriate byadding pharmaceutically acceptable acids or bases. If the preparationscomprise a pharmacologically active phosphonic acid, a base ispreferably added to adjust the pH values indicated above.

Examples of bases which can be used are: alkali metal or alkaline earthmetal hydroxides (e.g. NaOH, KOH; where appropriate in the form of theiraqueous solutions: sodium hydroxide solution, potassium hydroxidesolution), or basic phosphates, e.g. sodium phosphate, sodiumhydrogenphosphate, basic amino acids such as, for example, lysine,arginine, histidine, ornithine, citrulline, hydroxylysine, choline,meglumine, ethanolamines such as triethanolamine or else buffers(tris(hydroxymethyl)aminomethane, cyclohexylamino-1-propanesulphonicacid). The base preferably employed is: NaOH, KOH or arginine; NaOH isparticularly preferred, where appropriate as aqueous sodium hydroxidesolution.

Examples of acids which can be used are: inorganic acids such as, forexample, hydrochloric acid, sulphuric acid, phosphoric acid or organicacids such as, for example, methanesulphonic acid, formic acid, aceticacid, propionic acid, lactic acid, malonic acid, adipic acid, tartaricacid, oxalic acid, fumaric acid, malic acid, citric acid, succinic acid,aspartic acid, glutamic acid, gluconic acid, glucuronic acid,galacturonic acid, glutaric acid, lactobionic acid, mandelic acid,salicylic acid, ascorbic acid, benzoic acid, maleic acid, citric acid,octanoic acid, linoleic acid, linolenic acid.

The required amount of acid or base is governed by the desired pH.Normally the acid or base is used in a proportion of from 0.0001 to 20%,preferably 0.001 to 10%.

The acids can be used with a proportion of from 0.0001 to 20%,preferably 0.01 to 10%.

The medicaments of the invention can be manufactured by dispersing thevitamin in the solvent. The vitamin can be dispersed directly or, forquantitative conversion, by using a stock solution in the solvent. Apartfrom the actual solvent it is possible also to use other solvents asstock solution. Where appropriate, the pharmacologically acceptablephosphonic acid derivative is likewise dispersed in the solvent. Thebutanol or mixtures of butanol and solvent are added. Cosolvents andfurther ingredients such as, for example, antioxidants may have beenadded to the solvent or can be admixed later. The pH is adjusted, e.g.with a base. To protect the vitamin B₁₂, parts of the manufacture andfilling of the solutions can take place under a protective gasatmosphere, e.g. introducing nitrogen gas.

Alternatively, butanol and, where appropriate, also the phamacologicallyacceptable phosphonic acid derivative can initially be dissolved in thesolvent and then the vitamin B₁₂ can be added.

The pharmaceutical preparations according to the invention are generallysuitable for use in humans and animals. They are preferably employed inanimal management and animal breeding among productive and breedinglivestock, zoo, laboratory and experimental animals, and pets.

The productive and breeding livestock include mammals such as, forexample, cattle, horses, sheep, pigs, goats, camels, water buffaloes,donkeys, rabbits, fallow deer, reindeer, fur-bearing animals such as,for example, mink, chinchilla, racoon, and birds such as, for example,quail, chicken, geese, turkeys, ducks, pigeons and bird species forkeeping at home and in zoos.

Laboratory and experimental animals include mice, rats, guinea pigs,golden hamsters, rabbits, monkeys, dogs and cats.

Pets include rabbits, hamsters, rats, guinea pigs, mice, horses,reptiles, appropriate bird species, dogs and cats.

Mention may also be made of fish, specifically of productive, breeding,aquarium and ornamental fish of all ages which live in fresh water andsalt water.

In the case of pets, the preparations according to the invention arepreferably employed for horses, rabbits, cats and dogs. They areparticularly suitable for use in cats and dogs.

In the case of productive livestock, the preparations according to theinvention are preferably employed for cattle, sheep, pigs, goats,turkeys and chickens. Particularly preferred productive livestock arecattle and pigs.

Use is possible either prophylactically, metaphylactically ortherapeutically.

Liquid formulations according to the invention are preferably emulsionsor, in particular, solutions.

The formulations described herein can be supplied to the target organism(human or animal) in various ways. They can be administered for exampleparenterally, in particular by injection (e.g. subcutaneous,intramuscular, intravenous, intramammary, intraperitoneal), dermally,orally, rectally, vaginally or nasally, with preference for oral andparenteral administration—especially by injection. Parenteraladministration by injection is particularly preferred.

The use with the stated substances leads to medicaments having goodstability of vitamin B₁₂, especially to light.

EXAMPLES

The formulations of the following examples are produced by mixing ordissolving the stated ingredients in water for injections or distilledwater or demineralized water. To introduce the cyanocobalaminquantitatively into the main mixture it is advisable to use a stocksolution. This is not, however, obligatory. The pH of the solutions canbe adjusted by adding acids or bases. The solutions are produced andfilled under nitrogen protection. The solutions for injection aresterilized by filtration and transferred into suitable containers.Percentage data in percent by weight are based on the total volume ofthe finished product (M/V).

Example 1

-   -   10% Butaphosphan    -   0.005% cyanocobalamin (vitamin B₁₂)    -   3.0% n-butanol    -   quantum satis sodium hydroxide    -   ad 100% water for injections    -   0.0005 g of vitamin B₁₂ is dissolved in a partial quantity of        water for injections by heating. 1.0 g of butaphosphan and 0.3 g        of n-butanol are dissolved in water for injections and added to        the stock solution with cyanocobalamin. The pH is adjusted with        sodium hydroxide to 5.6 (+/−0.2), and the final weight is        adjusted to 10 ml with water for injections.

Example 2

-   -   0.005% Cyanocobalamin (vitamin B₁₂)    -   3.0% n-butanol    -   quantum satis sodium hydroxide    -   ad 100% water for injections    -   0.0010 g of vitamin B₁₂ is dissolved in a partial quantity of        water for injections by heating. 0.6 g of n-butanol are        dissolved in water for injections and added to the stock        solution with cyanocobalamin. The pH is adjusted with sodium        hydroxide to 5.6 (+/−0.2), and the final weight is adjusted to        20 ml with water for injections.

Example 3

-   -   10% Butaphosphan    -   0.005% cyanocobalamin (vitamin B₁₂)    -   2.0% n-butanol    -   quantum satis sodium hydroxide    -   ad 100% water for injections    -   0.0025 g of vitamin B₁₂ is dissolved in a partial quantity of        water for injections by heating. 5.0 g of butaphosphan and 1.0 g        of n-butanol are dissolved in water for injections and added to        the stock solution with cyanocobalamin. The pH is adjusted with        sodium hydroxide to 5.6 (+/−0.2), and the final weight is        adjusted to 50 ml with water for injections.

Example 4

-   -   20% Butaphosphan    -   0.010% cyanocobalamin (vitamin B₁₂)    -   3.0% n-butanol    -   quantum satis potassium hydroxide    -   ad 100% water for injections    -   0.0010 g of vitamin B₁₂ is dissolved in a partial quantity of        water for injections by heating. 2.0 g of butaphosphan and 0.3 g        of n-butanol are dissolved in water for injections and added to        the stock solution with cyanocobalamin. The pH is adjusted to        5.6 (+/−0.2), and the final weight is adjusted to 10 ml with        water for injections.

Example 5

-   -   10% Butaphosphan    -   0.005% cyanocobalamin (vitamin B₁₂)    -   4.0% n-butanol    -   quantum satis sodium hydroxide    -   ad 100% water for injections    -   0.005 g of vitamin B₁₂ is dissolved in a partial quantity of        water for injections by heating. 10.0 g of butaphosphan and 4.0        g of n-butanol are dissolved in water for injections and added        to the stock solution with cyanocobalamin. The pH is adjusted        with sodium hydroxide to 5.6 (+/−0.2), and the final weight is        adjusted to 100 ml with water for injections.

Example 6

-   -   15% Butaphosphan    -   0.0075% cyanocobalamin (vitamin B₁₂)    -   3.0% n-butanol    -   quantum satis meglumine    -   ad 100% water for injections    -   0.00075 g of vitamin B₁₂ is dissolved in a partial quantity of        water for injections by heating. 1.5 g of butaphosphan and 0.3 g        of n-butanol are dissolved in water for injections and added to        the stock solution with cyanocobalamin. The pH is adjusted with        meglumine to 5.6 (+/−0.2), and the final weight is adjusted to        10 ml with water for injections.

Example 7

-   -   30% Butaphosphan    -   0.015% cyanocobalamin (vitamin B₁₂)    -   3.0% n-butanol    -   quantum satis arginine    -   ad 100% water for injections    -   0.0015 g of vitamin B₁₂ is dissolved in a partial quantity of        water for injections by heating. 3.0 g of butaphosphan and 0.3 g        of n-butanol are dissolved in water for injections and added to        the stock solution with cyanocobalamin. The pH is adjusted with        arginine to 5.6 (+/−0.2), and the final weight is adjusted to 10        ml with water for injections.

Example 8

-   -   0.010% Cyanocobalamin (vitamin B₁₂)    -   3.0% n-butanol    -   quantum satis arginine    -   ad 100% water for injections    -   0.0010 g of vitamin B₁₂ is dissolved in a partial quantity of        water for injections by heating. 0.3 g of n-butanol is mixed        with water for injections and added to the stock solution with        cyanocobalamin. The pH is adjusted with arginine to 5.6        (+/−0.2), and the final weight is adjusted to 10 ml with water        for injections.

Stability to Light

The formulations described herein have shown an improved photostabilitycompared with other formulations. Selected examples thereof are listedin the following table. The results are depicted once again graphicallyin FIG. 1.

TABLE 1 Comparison of the photostabilities of a formulation withoutn-butanol (A) with a formulation with n-butanol (B). Vitamin B₁₂ contentInitial vitamin B₁₂ content in mg/100 ml in mg/100 ml after illuminationfor 3 h Formulation A 5.50 3.99 Formulation B 5.53 4.91 according toExample 1

What is claimed is:
 1. A photostable vitamin B₁₂ formulation comprising:0.001 to 0.01% m/V vitamin B₁₂; butaphosphan; 0.5 to 7% n-butanol m/V;and water, wherein the pH of the formulation is from about 4 to about 7.2. The formulation of claim 1 comprising from 1 to 5% m/V n-butanol. 3.The formulation of claim 1 comprising from 2 to 4% m/V n-butanol.
 4. Theformulation of claim 1 comprising from 0.005 to 0.01% m/V vitamin B₁₂.5. The formulation of claim 1 comprising from 1 to 30% m/V butaphosphan.6. The formulation of claim 1 comprising from 5 to 20% m/V butaphosphan.7. The formulation of claim 2 comprising from 5 to 20% m/V butaphosphan.8. The formulation of claim 1, wherein the pH of the formulation is5.6±0.2.
 9. The formulation of claim 7, wherein the pH of theformulation is 5.6±0.2.
 10. The formulation of claim 1, wherein vitaminB₁₂ is cyanocobalamin.
 11. The formulation of claim 7, wherein vitaminB₁₂ is cyanocobalamin.
 12. The formulation of claim 1 further comprisinga base.
 13. The formulation of claim 11 further comprising a base. 14.The formulation of claim 13, wherein the base comprises sodiumhydroxide.
 15. The formulation of claim 1, wherein water constitutesover 75% m/V of the formulation.
 16. The formulation of claim 11,wherein water constitutes over 75% m/V of the formulation.
 17. Theformulation of claim 1 further comprising a cosolvent.
 18. Theformulation of claim 1 further comprising an antioxidant, wetting agent,or combinations thereof.